It is now well documented that Crohn's disease is associated with a Th1 T cell-mediated inflammatory response and, as such, it is driven by the "master" Th1 cytokine(s), IL-12 (and possibly IL-23). Previous studies initially performed in this laboratory established that anti-IL-12 was an effective treatment of experimental mucosal inflammation due to a Th1-driven process. On this basis, we participated in the development of a fully human (monoclonal) anti-IL-12 (anti-p40) by Wyeth Pharmaceuticals for treatment of patients with Crohn's disease. This eventuated in a (phase I-II) double-blind, placebo-controlled trial of anti-IL-12 in 79 patients with active Crohn's disease studied at the NIH and other medical centers. In this study patients were randomly assigned to receive seven weekly subcutaneous injections of 1 or 3 mg/kg of anti-IL-12 or placebo with either a four week interval between the first and second injection (Cohort 1) or no interruption (Cohort 2). Patients in Cohort 2 receiving 3 mg/kg antibody showed significant differences in response rates (highest response rate 75% at week 6) and remission rates (highest remission rate 50% at week 19) compared to patients receiving placebo, whereas the high clinical response and remission rates in Cohort 1 patients receiving antibody were not significantly different from the placebo group. The effects of antibody treatment were durable and adverse events were comparable to placebo except for mild local injection reactions. In patients studied at the NIH, the effect of treatment on cytokine production by lamina propria cells extracted from biopsy speciments were studied. Anti-IL-12 treatment were accompanied by significant decreases in IL-12, IFN-gamma, IL-17, and TNF-alpha production, but no effect on IL-4 or IL-10 production. These studies show that monoclonal anti-IL-12 is an effective treatment of active Crohn's disease and pave the way for a phase III trial in a large patient cohort. In addition, it provides solid proof that a Th1 process is the final common T cell pathway of inflammation in Crohn's disease.